The present invention relates to biocompatible and biodegradable polymers. Particularly, the invention relates to biocompatible and biodegradable polyurethane foams. In several embodiments, the present invention relates to injectable polyurethane foams, to methods and compositions for their preparation and to the use of such foams as scaffolds for bone tissue engineering.
Synthetic biodegradable polymers are promising materials for bone tissue engineering. Many materials, including allografts, autografts, ceramics, polymers, and composites thereof are currently used as implants to repair damaged bone. Because of the risks of disease transmission and immunological response, the use of allograft bone is limited. Although autograft bone has the best capacity to stimulate healing of bone defects, explantation both introduces additional surgery pain and also risks donor-site morbidity. Synthetic polymers are advantageous because they can be designed with properties targeted for a given clinical application. Polymer scaffolds must support bone cell attachment, proliferation, and differentiation. Tuning the degradation rate with the rate of bone remodeling is an important consideration when selecting a synthetic polymer. Another important factor is the toxicity of the polymer and its degradation products. Furthermore, the polymer scaffold must be dimensionally and mechanically stable for a sufficient period of time to allow tissue ingrowth and bone remodeling.
Two-component reactive liquid polyurethanes designed for tissue repair have been disclosed. For example, U.S. Pat. No. 6,306,177, the disclosure of which is incorporate herein by reference, discloses a method for repairing a tissue site comprising the steps of providing a curable polyurethane composition, mixing the parts of the composition, and curing the composition in the tissue site wherein the composition is sufficiently flowable to permit injection by minimally invasive techniques and exhibits a tensile strength between 6,000 and 10,000 psi when cured. However, because this injectable polyurethane is non-porous and hard, tissue ingrowth is likely to be limited.
U.S. Pat. No. 6,376,742, the disclosure of which is incorporated herein by reference, discloses a method for in vivo tissue engineering comprising the steps of combining a flowable polymerizable composition including a blowing agent and delivering the resultant composition to a wound site via a minimally invasive surgical technique. U.S. Pat. No. 6,376,742 also discloses methods to prepare microcellular polyurethane implants as well as implants seeded with cells.
Bennett and co-workers prepared porous polyurethane implants for bone tissue engineering from isocyanate-terminated prepolymers, water, and a tertiary amine catalyst (diethylethanolamine). See, for example, Bennett S, Connolly K, Lee D R, Jiang Y, Buck D, Hollinger J O, Gruskin E A. Initial biocompatibility studies of a novel degradable polymeric bone substitute that hardens in situ. Bone 1996; 19(1, Supplement):10S-107S; U.S. Pat. Nos. 5,578,662, 6,207,767 and 6,339,130, the disclosures of which are incorporated herein by reference. The prepolymers were synthesized from lysine methyl ester diisocyanate (LDI) and poly(dioxanone-co-glycolide) from a pentaerythritol initiator and then combined with either hydroxyapatite or tricalcium phosphate to form a putty. Water and a tertiary amine were added to the putty prior to implantation in rats. The putty did not elicit an adverse tissue response following implantation.
Zhang and co-workers prepared biodegradable polyurethane foams from LDI, glucose, and poly(ethylene glycol). Zhang J, Doll B, Beckman E, Hollinger J O. A biodegradable polyurethane-ascorbic acid scaffold for bone tissue engineering. J. Biomed. Mater. Res. 2003; 67A(2):389-400; Zhang J, Doll B, Beckman J, Hollinger J O. Three-dimensional biocompatible ascorbic acid-containing scaffold for bone tissue engineering. Tissue Engineering 2003; 9(6):1143-1157; Zhang J-Y, Beckman E J, Hu J, Yuang G-G, Agarwal S, Hollinger J O. Synthesis, biodegradability, and biocompatibility of lysine diisocyanate-glucose polymers. Tissue Engineering 2002; 8(5):771-785; and Zhang J-Y, Beckman E J, Piesco N J, Agarwal S. A new peptide-based urethane polymer: synthesis, biodegradation, and potential to support cell growth in vitro. Biomaterials 2000; 21:1247-1258., the disclosures of which are incorporated herein by reference. The foams were synthesized by reacting isocyanate-terminated prepolymers with water in the absence of catalysts. The polyurethane foams supported the attachment, proliferation, and differentiation of bone marrow stromal cells in vitro and were non-immunogenic in vivo. Bioactive foams were also prepared by adding ascorbic acid to the water prior to adding the prepolymer. As the polymer degraded, ascorbic acid was released to the matrix, resulting in enhanced expression of osteogenic markers such as alkaline phosphatase and Type I collagen.
Published PCT international patent application WO 2004/009227 A2, the disclosure of which is incorporated herein by reference, claims a star prepolymer composition suitable as an injectable biomaterial for tissue engineering. The prepolymer is the reaction product of a diisocyanate and a starter molecule having a molecular weight preferably less than 400 Da. Porous scaffolds were prepared by adding low levels (e.g., <0.5 parts per hundred parts polyol) of water.
Copending Published US Patent Application No. 2005/0013793 (U.S. patent application Ser. No. 10/759,904), the disclosure of which is incorporated herein by reference, discloses inter alia a biocompatible and biodegradable polyurethane composition including at least one biologically active component with an active hydrogen atom capable of reacting with isocyanates. As the polyurethane degrades in vivo, the bioactive component is released to the extracellular matrix where it is, for example, taken up by cells.
While materials such as those described above are useful for bone tissue engineering, it is desirable to improve certain properties associated with injectable polyurethane scaffolds. Highly porous (e.g., >80% or even>85%), fast-rising (e.g., <30 minutes) conventional polyurethane foams have been manufactured commercially for years. For example, Ferrari and co-workers' in Ferrari R J, Sinner J W, Bill J C, Brucksch W F. Compounding polyurethanes: Humid aging can be controlled by choosing the right intermediate. Ind. Eng. Chem. 1958; 50(7):1041-1044, and U.S. Pat. No. 6,066,681, the disclosures of which is incorporated herein by reference, disclose methods for preparation of polyurethane foams from diisocyanates and polyester polyols. Catalysts, including organometallic compounds and tertiary amines, are added to balance the gelling (reaction of isocyanate with polyol) and blowing (reaction of isocyanate with water) reactions. Stabilizer, such as polyethersiloxanes and sulfated castor oil, are added to both emulsify the raw materials and stabilize the rising bubbles. Cell openers, such as powdered divalent salts of stearic acid, cause a local disruption of the pore structure during the foaming process, thereby yielding foams with a natural sponge structure. See Oertel G. Polyurethane Handbook. Berlin: Hanser Gardner Publications; 1994; Szycher, M, Szycher's Handbook of Polyurethanes, CRC Press, New York, N.Y., (1999), the disclosures of which are incorporated herein by reference. However, conventional polyurethane foams are not suitable for tissue engineering applications because they are prepared from toxic raw materials, such as aromatic diisocyanates and organotin catalysts.
Although progress has been made in the development of biocompatible and biodegradable polymers, it remains desirable to develop biocompatible and biodegradable polymers, methods of synthesizing such polymers, implantable devices comprising such polymers and methods of using such polymers.